Pseudorabies virus(PRV,SuidAlphaherpesvirus 1)causes substantial economic losses in swine production.Here,we report the development of DNA aptamers targeting the PRV glycoprotein D(gD)through an optimized SELEX protoc...Pseudorabies virus(PRV,SuidAlphaherpesvirus 1)causes substantial economic losses in swine production.Here,we report the development of DNA aptamers targeting the PRV glycoprotein D(gD)through an optimized SELEX protocol.After 15 selection cycles,Apt-gD-2 demonstrated nanomolar affinity(Kd=6.107±0.476 nM)and high specificity for gD,as validated by an enzyme-linked aptamer-sorbent assay(ELASA)and fluorescence microscopy.Molecular docking revealed hydrogen bonding as the key interaction mechanism.The developed ic-ELASA achieved 83.3%concordance with qPCR in clinical samples,supporting its utility for on-farm PRV surveillance.These findings highlight the potential of aptamer-based diagnostic methods for rapid,sensitive,and onsite detection of PRV,offering a promising tool for disease control in the swine industry.展开更多
Dear Editor,Myelin oligodendrocyte glycoprotein(MOG)is a minor component of myelin,expressed on the external surface of oligodendrocytes in the central nervous system(CNS)[1].Anti-MOG antibodies(MOG-ab)have been impli...Dear Editor,Myelin oligodendrocyte glycoprotein(MOG)is a minor component of myelin,expressed on the external surface of oligodendrocytes in the central nervous system(CNS)[1].Anti-MOG antibodies(MOG-ab)have been implicated in the demyelinating process and are considered unique biomarkers for a group of heterogeneous autoimmune inflammatory CNS diseases known as MOG-associated disorder(MOGAD)[1].MOGAD can present with a range of clinical manifestations,including optic neuritis,transverse myelitis,acute disseminating encephalomyelitis,and brainstem or cerebral encephalitis[1].Optic neuritis is the most common clinical feature of MOGAD in adults,typically manifesting as steroid-sensitive,recurrent,bilateral optic neuritis with optic disc swelling[1].展开更多
The invasion of host cells by the henipavirus is facilitated through the interaction between viral attachment(G)and fusion(F)glycoproteins with receptors on the cell surface.Langya henipavirus(LayV)was newly identifie...The invasion of host cells by the henipavirus is facilitated through the interaction between viral attachment(G)and fusion(F)glycoproteins with receptors on the cell surface.Langya henipavirus(LayV)was newly identified in China in 2022.The G proteins of LayV and Mojiang virus(MojV)exhibit high amino acid homology(86%),while they are located in a unique evolutionary clade within the Henipavirus genus.In this study,the crystal structure of the LayV G protein was resolved at a 3.37Åresolution,revealing a head domain with sixβ-propeller-like domains distinct from other henipavirus G proteins,such as those of Nipah virus(NiV)and Hendra virus(HeV).Furthermore,the prominent loop in the center cavity of the LayV G protein showed unique structural features.In the ELISA and SPR assays,the LayV G protein was unable to bind to the existing henipavirus-neutralizing antibodies or the ephrin-B2 receptor.Immunogenicity studies in mice demonstrated robust antibody responses elicited by the LayV G protein.These antibodies exhibited strong reactivity against both LayV and MojV G proteins.However,only weak cross-reactivity was observed with other henipaviruses.Moreover,eight monoclonal antibodies targeting the LayV G protein were generated,two of which exhibited broad binding activity across different henipavirus G proteins.These findings underscore the need for tailored vaccines and therapeutics for LayV and related novel henipaviruses.展开更多
The study by Ohno et al provides valuable insights into the role of leucine-rich alpha-2-glycoprotein(LRG)as a potential biomarker for identifying small bowel lesions in Crohn's disease(CD).However,several methodo...The study by Ohno et al provides valuable insights into the role of leucine-rich alpha-2-glycoprotein(LRG)as a potential biomarker for identifying small bowel lesions in Crohn's disease(CD).However,several methodological challenges hinder its immediate use in clinical practice.Notably,the current research was retrospective,lacks comparative studies with fecal calprotectin,and did not provide long-term predictive data.Further prospective studies are needed to improve the applicability of LRG.Moreover,integrating LRG with additional biomarkers and employing artificial intelligence techniques may improve its effectiveness in disease monitoring.Future research should address interobserver variability,assess LRG's cost-effectiveness,and standardize endoscopic healing definitions to ensure broader applicability.Advancing these areas is vital for establishing LRG's role in precision medicine strategies for the management of CD.展开更多
BACKGROUND Achievement of endoscopic healing(EH)is significant in the clinical practice of inflammatory bowel disease as it is correlated with improved prognosis.Existing biomarkers,including C-reactive protein(CRP),h...BACKGROUND Achievement of endoscopic healing(EH)is significant in the clinical practice of inflammatory bowel disease as it is correlated with improved prognosis.Existing biomarkers,including C-reactive protein(CRP),have relatively low accuracy for predicting EH,especially in small intestinal lesions in Crohn’s disease(CD);thus,noninvasive and more accurate biomarkers are required.Leucine-rich alpha-2 glycoprotein(LRG),a 50-kD protein,is produced under inflammatory conditions and has been reported to be useful in assessing disease activity in inflammatory bowel disease.However,the usefulness of LRG in small intestinal lesions in CD remains inconclusive.AIM To determine the usefulness of LRG for EH in small bowel lesions in CD and compare it with CRP.METHODS This study included 133 consecutive patients with CD who underwent balloonassisted enteroscopy between June 2021 and March 2024 at Shiga University of Medical Science Hospital(Otsu,Japan).We retrospectively analyzed endoscopic scores in each of the ileum and colon and four markers including LRG,CRP,albumin,and Harvey-Bradshaw index(HBI).Spearman’s rank correlation coefficient and receiver operating characteristic analysis were performed.RESULTS Either active ileal or colonic lesions exhibited significant differences in LRG,CRP,albumin,and HBI compared with EH.CRP,albumin,and HBI showed a worse correlation with endoscopic activity in the ileum than that in the colon;however,LRG did not show a worse correlation(colon,r=0.5218;ileum,r=0.5602).Receiver operating characteristic analysis revealed that LRG for EH in the ileum and colon had the same cutoff values of 12.4μg/mL.Comparing the areas under the curve of LRG and CRP for predicting EH in the ileum revealed a significantly higher areas under the curve of LRG(95%confidence interval,0.017-0.194;P=0.024),whereas the two showed no significant difference in the colon.CONCLUSION LRG is a useful biomarker in assessing the endoscopic activity of CD and is more useful than CRP in the small intestine.展开更多
Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system...Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system,and cell membranes and to reveal the effects of SV2A on APP amyloid degradation.Methods Colocalization analysis of APP with specific tagged proteins in the TGN,ensolysosomal system,and cell membrane was performed to explore the effects of SV2A on the intracellular transport of APP.APP,β-site amyloid precursor protein cleaving enzyme 1(BACE1)expressions,and APP cleavage products levels were investigated to observe the effects of SV2A on APP amyloidogenic processing.Results APP localization was reduced in the TGN,early endosomes,late endosomes,and lysosomes,whereas it was increased in the recycling endosomes and cell membrane of SV2A-overexpressed neurons.Moreover,Arl5b(ADP-ribosylation factor 5b),a protein responsible for transporting APP from the TGN to early endosomes,was upregulated by SV2A.SV2A overexpression also decreased APP transport from the cell membrane to early endosomes by downregulating APP endocytosis.In addition,products of APP amyloid degradation,including sAPPβ,Aβ1-42,and Aβ1-40,were decreased in SV2A-overexpressed cells.Conclusion These results demonstrated that SV2A promotes APP transport from the TGN to early endosomes by upregulating Arl5b and promoting APP transport from early endosomes to recycling endosomes-cell membrane pathway,which slows APP amyloid degradation.展开更多
Herpes simplex virus 2(HSV-2)is a major pathogen causing neonatal herpes and increasing the risk of human immunodeficiency virus 1(HIV-1)infection.However,the mechanisms underlying host restriction of HSV-2 infection ...Herpes simplex virus 2(HSV-2)is a major pathogen causing neonatal herpes and increasing the risk of human immunodeficiency virus 1(HIV-1)infection.However,the mechanisms underlying host restriction of HSV-2 infection are still not fully understood.The ubiquitously expressed transcript isoform 2(UXT-V2),anα-type prefoldin protein,functions as a versatile transcription factor associated with numerous human tumors,but its role in viral infection remains unclear.In this study,we found that ectopic expression of UXT-V2 significantly inhibited HSV-2 replication,while knockout of endogenously expressed UXT-V2 promoted HSV-2 proliferation.Further analysis revealed that UXT-V2 restricts HSV-2 replication independent of its role in regulating NF-κB.In the context of HSV--2 infection or in viral glycoprotein B(gB)-transfected cells,UXT-V2 facilitates K48-linked ubiquitination of gB,leading to its degradation via the proteasome pathway,thereby inhibiting viral replication.Furthermore,we identified that UXT-V2 interacts with gB,recruiting the E3 ligase TRIM21 to facilitate K48-linked ubiquitination of gB.HSV-2,in turn,reduces the abundance of UXT-V2 proteins both in vitro and in mice,highlighting the complexity of HSV-2-host interactions.Collectively,our findings,for the first time,demonstrate an anti-HSV-2 role of UXT-V2,unveiling a novel host immune defense mechanism involved in regulating glycoprotein homeostasis.展开更多
Nipah virus(NiV)and Hendra virus(HeV)are highly pathogenic henipaviruses within the Paramyxoviridae family,causing severe respiratory and neurological diseases in humans and animals with fatality rates up to 75%,and n...Nipah virus(NiV)and Hendra virus(HeV)are highly pathogenic henipaviruses within the Paramyxoviridae family,causing severe respiratory and neurological diseases in humans and animals with fatality rates up to 75%,and no licensed human vaccines or therapeutics.In this study,we identified a unique vulnerable epitope on the NiV attachment glycoprotein(G)recognized by the potent neutralizing antibody 14F8,which targets a receptor-binding site and neutralizes NiV effectively.Using the 2.8Åcrystal structure of the 14F8 Fab–NiV-G complex as a guide,we reconstructed this epitope on HeV-G via a single amino acid substitution(S586N),creating the HeV-G_(S586N) mutant.Immunization with HeV-G_(S586N) in BALB/c mice and cynomolgus monkeys elicited robust,broadly neutralizing antibody responses against both NiV and HeV,achieving higher NiV-neutralizing titers post-prime compared to wild-type HeV-G,as confirmed by pseudovirus and live-virus assays.Crystal structures of HeV-G_(S586N)(3.3Å)and its 14F8 complex(3.2Å)showed the S586N substitution induced a 9Åconformational rearrangement inβ-propeller blade 6,reshaping the molecular skeleton and solvent-accessible surface without direct N586–14F8 interaction,thus mimicking the NiV epitope.These findings position HeV-G_(S586N) as a promising broad-spectrum antigen for henipavirus prevention and demonstrate the value of structure-guided epitope reconstruction in universal vaccine design for emerging viral threats.展开更多
BACKGROUND Cases of myelin oligodendrocyte glycoprotein(MOG)antibody-related disease have a history of coronavirus disease 2019 infection or its vaccination before disease onset.Severe acute respiratory syndrome virus...BACKGROUND Cases of myelin oligodendrocyte glycoprotein(MOG)antibody-related disease have a history of coronavirus disease 2019 infection or its vaccination before disease onset.Severe acute respiratory syndrome virus 2(SARS-CoV-2)infection has been considered to be a trigger of central nervous system autoimmune diseases.CASE SUMMARY Here we report a 20-year male with MOG-associated transverse myelitis after a SARS-CoV-2 infection.The patient received a near-complete recovery after standard immunological treatments.CONCLUSION Attention should be paid to the evaluation of typical or atypical neurological symptoms that may be triggered by SARS-CoV-2 infection.展开更多
Lassa virus(LASV)is an enveloped,negative-sense RNA virus that causes Lassa hemorrhagic fever.Successful entry of LASV requires the viral glycoprotein 1(GP1)to undergo a receptor switch from its primary receptor alpha...Lassa virus(LASV)is an enveloped,negative-sense RNA virus that causes Lassa hemorrhagic fever.Successful entry of LASV requires the viral glycoprotein 1(GP1)to undergo a receptor switch from its primary receptor alpha-dystroglycan(α-DG)to its endosomal receptor lysosome-associated membrane protein 1(LAMP1).A conserved histidine triad in LASV GP1 has been reported to be responsible for receptor switch.To test the hypothesis that other non-conserved residues also contribute to receptor switch,we constructed a series of mutant LASV GP1 proteins and tested them for binding to LAMP1.Four residues,L84,K88,L107,and H170,were identified as critical for receptor switch.Substituting any of the four residues with the corresponding lymphocytic choriomeningitis virus(LCMV)residue(L84 N,K88E,L10F,and H170S)reduced the binding affinity of LASV GP1 for LAMP1.Moreover,all mutations caused decreases in glycoprotein precursor(GPC)-mediated membrane fusion at both pH 4.5 and 5.2.The infectivity of pseudotyped viruses bearing either GPCL84N or GPCK88E decreased sharply in multiple cell types,while L107F and H170S had only mild effects on infectivity.Using biolayer light interferometry assay,we found that all four mutants had decreased binding affinity to LAMP1,in the order of binding affinity being L84 N>L107F>K88E>H170S.The four amino acid loci identified for the first time in this study have important reference significance for the in-depth investigation of the mechanism of receptor switching and immune escape of LASV occurrence and the development of reserve anti-LASV infection drugs.展开更多
Nasopharyngeal carcinoma(NPC)is a malignant tumor arising from the nasopharyngeal epithelium.It consists of undifferentiated squamous cells in the nasopharynx.This type of epithelial cell neoplasm is globally distribu...Nasopharyngeal carcinoma(NPC)is a malignant tumor arising from the nasopharyngeal epithelium.It consists of undifferentiated squamous cells in the nasopharynx.This type of epithelial cell neoplasm is globally distributed,with the highest prevalence observed in certain regions of the world.It has been known since ancient times.The incidence of NPC is steadily decreasing as data on the molecular factors involved in the pathogenesis of NPC accumulate.Glycoproteins are characterized by polymers of saccharides attached to the amino acid sequences of proteins during the process of glycosylation.They are present in all animal cells and are especially abundant on the surface of tumor cells.Alterations in expression of cellular glycoproteins have recently attracted attention as a key component of neoplastic progression.Tumor-associated glycoproteins may serve as a hallmark of cancer cells and thus represent novel diagnostic and even therapeutic targets.Interest in the role of glycoproteins in cancer in general and specifically in NPC pathology has steadily increased over the past fifty years,reaching over thousands and two hundred publications in the last five years,respectively.Here,data on a specific class of proteins,glycoproteins,involved in tumorigenesis of NPCs are summarized,with a focus on a few of the best-studied ones.Relevant studies performed mainly in the last five years were retrieved and collected through the PubMed system.展开更多
介绍了一个新的基于优化推导出的核偏最小二乘(kernel partial least squares,K-PLS)的算法原理和实现步骤,并且给出了利用K-PLS法构建P-糖蛋白(P-glycoprotein,P-gp)黄酮类抑制剂的定量构效关系(QSAR)模型.利用该方法结合几个简单的分...介绍了一个新的基于优化推导出的核偏最小二乘(kernel partial least squares,K-PLS)的算法原理和实现步骤,并且给出了利用K-PLS法构建P-糖蛋白(P-glycoprotein,P-gp)黄酮类抑制剂的定量构效关系(QSAR)模型.利用该方法结合几个简单的分子拓扑参数,构建了具有高准确率的预测模型.该模型将有助于P-gp黄酮类抑制剂的虚拟筛选和理性设计.结果证明K-PLS是一个十分稳定可靠的方法,将会在化学计量学领域得到较好的应用和推广.展开更多
肿瘤多药耐药性(multiple drug resistance,MDR)的发生往往伴随着多药耐药基因如MDR1、MRP1和BCRP等高表达,其中MDR1基因编码的P-糖蛋白(P-glycoprotein,P-gp)是目前公认可以诱发癌细胞发生MDR的重要分子。传统研究认为P-gp主要是作为...肿瘤多药耐药性(multiple drug resistance,MDR)的发生往往伴随着多药耐药基因如MDR1、MRP1和BCRP等高表达,其中MDR1基因编码的P-糖蛋白(P-glycoprotein,P-gp)是目前公认可以诱发癌细胞发生MDR的重要分子。传统研究认为P-gp主要是作为一个药物泵将化疗药物从细胞内排出从而导致MDR。然而系列研究发现,除了介导MDR以外,P-gp还能够调节癌细胞的生长、增殖、凋亡、迁移和侵袭等其他生物学行为;而且研究表明P-gp的这些作用可以依赖,也可以不依赖于其药物泵的功能。这些结果表明P-gp能够通过一些新的机制促进肿瘤的进展。本文主要针对P-gp在促进肿瘤进展中的作用进行综述。展开更多
Myelin-associated glycoprotein（MAG） inhibits the growth of neurites from nerve cells. Extraction and purification of MAG require complex operations; therefore, we attempted to determine whether commercially availabl...Myelin-associated glycoprotein（MAG） inhibits the growth of neurites from nerve cells. Extraction and purification of MAG require complex operations; therefore, we attempted to determine whether commercially available MAG-Fc can replace endogenous MAG for research purposes. Immunofluorescence using specific antibodies against MAG, Nogo receptor（NgR） and paired immunoglobulin-like receptor B（PirB） was used to determine whether MAG-Fc can be endocytosed by neuro-2a cells. In addition, neurite outgrowth of neuro-2a cells treated with different doses of MAG-Fc was evaluated. Enzyme linked immunosorbent assays were used to measure RhoA activity. Western blot assays were conducted to assess Rho-associated protein kinase（ROCK） phosphorylation. Neuro-2a cells expressed NgR and PirB, and MAG-Fc could be endocytosed by binding to NgR and PirB. This activated intracellular signaling pathways to increase RhoA activity and ROCK phosphorylation, ultimately inhibiting neurite outgrowth. These findings not only verify that MAG-Fc can inhibit the growth of neural neurites by activating RhoA signaling pathways, similarly to endogenous MAG, but also clearly demonstrate that commercial MAG-Fc is suitable for experimental studies of neurite outgrowth.展开更多
Estrus-associated glycoprotein (EGP) is a special protein in oviductal fluid which appears before ovulation and fertilization and disappears after the embryo passes into the uterus. One-and two dimensional SDS-PAGE an...Estrus-associated glycoprotein (EGP) is a special protein in oviductal fluid which appears before ovulation and fertilization and disappears after the embryo passes into the uterus. One-and two dimensional SDS-PAGE and Western blotting with monoclonal antibody or peanut agglutinin were used to characterize the glycoprotein,The specificity of the marking agents enabled the study to proceed without purification. EGP was found to include two proteins: one is acidic with a pH of 4.5 while the other is basic with a pH of 8.0 The molecular weights of their subunits are the same, that is 110 kD. This study may shed light on the mechanism of reproductive Process and be helpful to the development of a more cffective culture medium for in vitro culture of early embryo.展开更多
Immunoglobulin G against myelin oligodendrocyte glycoprotein(MOG-Ig G) is detectable in neuromyelitis optica spectrum disorder(NMOSD) without aquaporin-4 Ig G(AQP4-Ig G), but its pathogenicity remains unclear.In this ...Immunoglobulin G against myelin oligodendrocyte glycoprotein(MOG-Ig G) is detectable in neuromyelitis optica spectrum disorder(NMOSD) without aquaporin-4 Ig G(AQP4-Ig G), but its pathogenicity remains unclear.In this study, we explored the pathogenic mechanisms of MOG-Ig G in vitro and in vivo and compared them with those of AQP4-Ig G. MOG-Ig G-positive serum induced complement activation and cell death in human embryonic kidney(HEK)-293 T cells transfected with human MOG. In C57 BL/6 mice and Sprague-Dawley rats, MOG-Ig G only caused lesions in the presence of complement. Interestingly, AQP4-Ig G induced astroglial damage, while MOGIg G mainly caused myelin loss. MOG-Ig G also induced astrocyte damage in mouse brains in the presence ofcomplement. Importantly, we also observed ultrastructural changes induced by MOG-Ig G and AQP4-Ig G. These findings suggest that MOG-Ig G directly mediates cell death by activating complement in vitro and producing NMOSDlike lesions in vivo. AQP4-Ig G directly targets astrocytes,while MOG-Ig G mainly damages oligodendrocytes.展开更多
During mammalian fertilisation, the zona pellucida （ZP） matrix surrounding the oocyte is responsible for the binding of the spermatozoa to the oocyte and induction of the acrosome reaction （AR） in the ZP-bound spe...During mammalian fertilisation, the zona pellucida （ZP） matrix surrounding the oocyte is responsible for the binding of the spermatozoa to the oocyte and induction of the acrosome reaction （AR） in the ZP-bound spermatozoon. The AR is crucial for the penetration of the ZP matrix by spermatozoa. The ZP matrix in mice is composed of three glycoproteins designated ZP1, ZP2 and ZP3, whereas in humans, it is composed of four （ZP1, ZP2, ZP3 and ZP4）. ZP3 acts as the putative primary sperm receptor and is responsible for AR induction in mice, whereas in humans （in addition to ZP3）, ZP1 and ZP4 also induce the AR. The ability of ZP3 to induce the AR resides in its C-terminal fragment. O-linked glycans are critical for the murine ZP3-mediated AR. However, N-linked glycans of human ZP1, ZP3 and ZP4 have important roles in the induction of the AR. Studies with pharmacological inhibitors showed that the ZP3-induced AR involves the activation of the Gi-coupled receptor pathway, whereas ZP1- and ZP4-mediated ARs are independent of this pathway. The ZP3-induced AR involves the activation of T-type voltage-operated calcium channels （VOCCs）, whereas ZP1- and ZP4-induced ARs involve both T- and L-type VOCCs. To conclude, in mice, ZP3 is primarily responsible for the binding of capacitated spermatozoa to the ZP matrix and induction of the AR, whereas in humans （in addition to ZP3）, ZP1 and ZP4 also participate in these stages of fertilisation.展开更多
Gynogenetic silver crucian carp, Carassius auratus gibelio, is an intriguing model system. In the present work, a systemic study has been initiated by introducing suppression subtractive hybridization technique into t...Gynogenetic silver crucian carp, Carassius auratus gibelio, is an intriguing model system. In the present work, a systemic study has been initiated by introducing suppression subtractive hybridization technique into this model system to identify the differentially expressed genes in oocytes between gynogenetic silver crucian carp and its closely related gonochoristic color crucian carp. Five differential cDNA fragments were identified from the preliminary screening, and two of them are ZP3 homologues. Moreover, the full length ZP3 cDNAs were cloned from their oocyte cDNA libraries. The length of ZP3 cDNAs were 1378 bp for gyno-carp and 1367 bp for gono-carp, and they can be translated into proteins with 435 amino acids. Obvious differences are not only in the composition of amino acids, but also in the number of potential O-linked oligosaccharide sites. In addition, gyno-carp ZP3 amino acid sequence has an unexpected higher identity value with common carp (83.5%) than that with the closely related gono-carp (74.7%). The unique homology may be originated from the ancient hybridization. Northern blot analysis confirmed that expression of the ZP3 gene occurred exclusively in the oocytes. Because O-linked oligosaccharides on ZP3 have been demonstrated to play very important roles in fertilization, it is suggested that the extra O-linked glycosylation sites may be related to the unique sperm-egg recognition mechanism in gynogenesis.展开更多
基金supported by the Henan Provincial Science and Technology Research Project(Grant No.242102110019)the National Natural Science Foundation of China(Grant No.31972672).
文摘Pseudorabies virus(PRV,SuidAlphaherpesvirus 1)causes substantial economic losses in swine production.Here,we report the development of DNA aptamers targeting the PRV glycoprotein D(gD)through an optimized SELEX protocol.After 15 selection cycles,Apt-gD-2 demonstrated nanomolar affinity(Kd=6.107±0.476 nM)and high specificity for gD,as validated by an enzyme-linked aptamer-sorbent assay(ELASA)and fluorescence microscopy.Molecular docking revealed hydrogen bonding as the key interaction mechanism.The developed ic-ELASA achieved 83.3%concordance with qPCR in clinical samples,supporting its utility for on-farm PRV surveillance.These findings highlight the potential of aptamer-based diagnostic methods for rapid,sensitive,and onsite detection of PRV,offering a promising tool for disease control in the swine industry.
文摘Dear Editor,Myelin oligodendrocyte glycoprotein(MOG)is a minor component of myelin,expressed on the external surface of oligodendrocytes in the central nervous system(CNS)[1].Anti-MOG antibodies(MOG-ab)have been implicated in the demyelinating process and are considered unique biomarkers for a group of heterogeneous autoimmune inflammatory CNS diseases known as MOG-associated disorder(MOGAD)[1].MOGAD can present with a range of clinical manifestations,including optic neuritis,transverse myelitis,acute disseminating encephalomyelitis,and brainstem or cerebral encephalitis[1].Optic neuritis is the most common clinical feature of MOGAD in adults,typically manifesting as steroid-sensitive,recurrent,bilateral optic neuritis with optic disc swelling[1].
基金the funding support from the National Natural Science Foundation of China(32200762).
文摘The invasion of host cells by the henipavirus is facilitated through the interaction between viral attachment(G)and fusion(F)glycoproteins with receptors on the cell surface.Langya henipavirus(LayV)was newly identified in China in 2022.The G proteins of LayV and Mojiang virus(MojV)exhibit high amino acid homology(86%),while they are located in a unique evolutionary clade within the Henipavirus genus.In this study,the crystal structure of the LayV G protein was resolved at a 3.37Åresolution,revealing a head domain with sixβ-propeller-like domains distinct from other henipavirus G proteins,such as those of Nipah virus(NiV)and Hendra virus(HeV).Furthermore,the prominent loop in the center cavity of the LayV G protein showed unique structural features.In the ELISA and SPR assays,the LayV G protein was unable to bind to the existing henipavirus-neutralizing antibodies or the ephrin-B2 receptor.Immunogenicity studies in mice demonstrated robust antibody responses elicited by the LayV G protein.These antibodies exhibited strong reactivity against both LayV and MojV G proteins.However,only weak cross-reactivity was observed with other henipaviruses.Moreover,eight monoclonal antibodies targeting the LayV G protein were generated,two of which exhibited broad binding activity across different henipavirus G proteins.These findings underscore the need for tailored vaccines and therapeutics for LayV and related novel henipaviruses.
文摘The study by Ohno et al provides valuable insights into the role of leucine-rich alpha-2-glycoprotein(LRG)as a potential biomarker for identifying small bowel lesions in Crohn's disease(CD).However,several methodological challenges hinder its immediate use in clinical practice.Notably,the current research was retrospective,lacks comparative studies with fecal calprotectin,and did not provide long-term predictive data.Further prospective studies are needed to improve the applicability of LRG.Moreover,integrating LRG with additional biomarkers and employing artificial intelligence techniques may improve its effectiveness in disease monitoring.Future research should address interobserver variability,assess LRG's cost-effectiveness,and standardize endoscopic healing definitions to ensure broader applicability.Advancing these areas is vital for establishing LRG's role in precision medicine strategies for the management of CD.
基金Supported by the Grants-in-Aid for Scientific Research from the Ministry of Education,Culture,Sports,Science,and Technology of Japan,No.21K15947 and No.23K07435.
文摘BACKGROUND Achievement of endoscopic healing(EH)is significant in the clinical practice of inflammatory bowel disease as it is correlated with improved prognosis.Existing biomarkers,including C-reactive protein(CRP),have relatively low accuracy for predicting EH,especially in small intestinal lesions in Crohn’s disease(CD);thus,noninvasive and more accurate biomarkers are required.Leucine-rich alpha-2 glycoprotein(LRG),a 50-kD protein,is produced under inflammatory conditions and has been reported to be useful in assessing disease activity in inflammatory bowel disease.However,the usefulness of LRG in small intestinal lesions in CD remains inconclusive.AIM To determine the usefulness of LRG for EH in small bowel lesions in CD and compare it with CRP.METHODS This study included 133 consecutive patients with CD who underwent balloonassisted enteroscopy between June 2021 and March 2024 at Shiga University of Medical Science Hospital(Otsu,Japan).We retrospectively analyzed endoscopic scores in each of the ileum and colon and four markers including LRG,CRP,albumin,and Harvey-Bradshaw index(HBI).Spearman’s rank correlation coefficient and receiver operating characteristic analysis were performed.RESULTS Either active ileal or colonic lesions exhibited significant differences in LRG,CRP,albumin,and HBI compared with EH.CRP,albumin,and HBI showed a worse correlation with endoscopic activity in the ileum than that in the colon;however,LRG did not show a worse correlation(colon,r=0.5218;ileum,r=0.5602).Receiver operating characteristic analysis revealed that LRG for EH in the ileum and colon had the same cutoff values of 12.4μg/mL.Comparing the areas under the curve of LRG and CRP for predicting EH in the ileum revealed a significantly higher areas under the curve of LRG(95%confidence interval,0.017-0.194;P=0.024),whereas the two showed no significant difference in the colon.CONCLUSION LRG is a useful biomarker in assessing the endoscopic activity of CD and is more useful than CRP in the small intestine.
基金supported by grants from the State Key Program of the National Natural Science Foundation of China(grant number 82030064)Beijing Hospital Authority Youth Program(grant number QML20230812)+2 种基金Research and Development Foundation of Capital Medical University(grant number PYZ23052)National Natural Science Youth Cultivation Project of Xuanwu Hospital,Capital Medical University(grant number QNPY202317)Capital Medical University Research and Cultivation Fund(grant number PYZ23049).
文摘Objective To reveal the effects and potential mechanisms by which synaptic vesicle glycoprotein 2A(SV2A)influences the distribution of amyloid precursor protein(APP)in the trans-Golgi network(TGN),endolysosomal system,and cell membranes and to reveal the effects of SV2A on APP amyloid degradation.Methods Colocalization analysis of APP with specific tagged proteins in the TGN,ensolysosomal system,and cell membrane was performed to explore the effects of SV2A on the intracellular transport of APP.APP,β-site amyloid precursor protein cleaving enzyme 1(BACE1)expressions,and APP cleavage products levels were investigated to observe the effects of SV2A on APP amyloidogenic processing.Results APP localization was reduced in the TGN,early endosomes,late endosomes,and lysosomes,whereas it was increased in the recycling endosomes and cell membrane of SV2A-overexpressed neurons.Moreover,Arl5b(ADP-ribosylation factor 5b),a protein responsible for transporting APP from the TGN to early endosomes,was upregulated by SV2A.SV2A overexpression also decreased APP transport from the cell membrane to early endosomes by downregulating APP endocytosis.In addition,products of APP amyloid degradation,including sAPPβ,Aβ1-42,and Aβ1-40,were decreased in SV2A-overexpressed cells.Conclusion These results demonstrated that SV2A promotes APP transport from the TGN to early endosomes by upregulating Arl5b and promoting APP transport from early endosomes to recycling endosomes-cell membrane pathway,which slows APP amyloid degradation.
基金supported by the National Natural Science Foundation of China(82472272 and 82171736)the National Key Research and Development Program of China(2022YFC2304301 and 2023YFC2306600).
文摘Herpes simplex virus 2(HSV-2)is a major pathogen causing neonatal herpes and increasing the risk of human immunodeficiency virus 1(HIV-1)infection.However,the mechanisms underlying host restriction of HSV-2 infection are still not fully understood.The ubiquitously expressed transcript isoform 2(UXT-V2),anα-type prefoldin protein,functions as a versatile transcription factor associated with numerous human tumors,but its role in viral infection remains unclear.In this study,we found that ectopic expression of UXT-V2 significantly inhibited HSV-2 replication,while knockout of endogenously expressed UXT-V2 promoted HSV-2 proliferation.Further analysis revealed that UXT-V2 restricts HSV-2 replication independent of its role in regulating NF-κB.In the context of HSV--2 infection or in viral glycoprotein B(gB)-transfected cells,UXT-V2 facilitates K48-linked ubiquitination of gB,leading to its degradation via the proteasome pathway,thereby inhibiting viral replication.Furthermore,we identified that UXT-V2 interacts with gB,recruiting the E3 ligase TRIM21 to facilitate K48-linked ubiquitination of gB.HSV-2,in turn,reduces the abundance of UXT-V2 proteins both in vitro and in mice,highlighting the complexity of HSV-2-host interactions.Collectively,our findings,for the first time,demonstrate an anti-HSV-2 role of UXT-V2,unveiling a novel host immune defense mechanism involved in regulating glycoprotein homeostasis.
基金funding support from the National Natural Science Foundation of China(32200762)the Defense Industrial Technology Development Program(JCKY2020802B001).
文摘Nipah virus(NiV)and Hendra virus(HeV)are highly pathogenic henipaviruses within the Paramyxoviridae family,causing severe respiratory and neurological diseases in humans and animals with fatality rates up to 75%,and no licensed human vaccines or therapeutics.In this study,we identified a unique vulnerable epitope on the NiV attachment glycoprotein(G)recognized by the potent neutralizing antibody 14F8,which targets a receptor-binding site and neutralizes NiV effectively.Using the 2.8Åcrystal structure of the 14F8 Fab–NiV-G complex as a guide,we reconstructed this epitope on HeV-G via a single amino acid substitution(S586N),creating the HeV-G_(S586N) mutant.Immunization with HeV-G_(S586N) in BALB/c mice and cynomolgus monkeys elicited robust,broadly neutralizing antibody responses against both NiV and HeV,achieving higher NiV-neutralizing titers post-prime compared to wild-type HeV-G,as confirmed by pseudovirus and live-virus assays.Crystal structures of HeV-G_(S586N)(3.3Å)and its 14F8 complex(3.2Å)showed the S586N substitution induced a 9Åconformational rearrangement inβ-propeller blade 6,reshaping the molecular skeleton and solvent-accessible surface without direct N586–14F8 interaction,thus mimicking the NiV epitope.These findings position HeV-G_(S586N) as a promising broad-spectrum antigen for henipavirus prevention and demonstrate the value of structure-guided epitope reconstruction in universal vaccine design for emerging viral threats.
基金Supported by the Shenzhen University Teaching Reform Fund,No.JG2023166the Shenzhen Science and Technology Innovation Commission Fund,No.JCYJ2022081802810022the Shenzhen Science and Technology Innovation Commission Basic Research Key Projects Fund,No.JCYJ20210324115800003.
文摘BACKGROUND Cases of myelin oligodendrocyte glycoprotein(MOG)antibody-related disease have a history of coronavirus disease 2019 infection or its vaccination before disease onset.Severe acute respiratory syndrome virus 2(SARS-CoV-2)infection has been considered to be a trigger of central nervous system autoimmune diseases.CASE SUMMARY Here we report a 20-year male with MOG-associated transverse myelitis after a SARS-CoV-2 infection.The patient received a near-complete recovery after standard immunological treatments.CONCLUSION Attention should be paid to the evaluation of typical or atypical neurological symptoms that may be triggered by SARS-CoV-2 infection.
基金supported by the National Key Research and Development Program of China(2023YFC2605504,2022YFC2303300)the National Natural Sciences Foundation of China(82172273 and 31670165)+3 种基金the Open Research Fund Program of the State Key Laboratory of Virology of China(2023JZZD-01)the Health research project of Shaanxi Province(2022D040)the Science and Technology Planning Project of Shaanxi Provincial Education Department(22JK0545)the Natural Science Basic Research Program of Shaanxi(2024JC-YBQN-0922).
文摘Lassa virus(LASV)is an enveloped,negative-sense RNA virus that causes Lassa hemorrhagic fever.Successful entry of LASV requires the viral glycoprotein 1(GP1)to undergo a receptor switch from its primary receptor alpha-dystroglycan(α-DG)to its endosomal receptor lysosome-associated membrane protein 1(LAMP1).A conserved histidine triad in LASV GP1 has been reported to be responsible for receptor switch.To test the hypothesis that other non-conserved residues also contribute to receptor switch,we constructed a series of mutant LASV GP1 proteins and tested them for binding to LAMP1.Four residues,L84,K88,L107,and H170,were identified as critical for receptor switch.Substituting any of the four residues with the corresponding lymphocytic choriomeningitis virus(LCMV)residue(L84 N,K88E,L10F,and H170S)reduced the binding affinity of LASV GP1 for LAMP1.Moreover,all mutations caused decreases in glycoprotein precursor(GPC)-mediated membrane fusion at both pH 4.5 and 5.2.The infectivity of pseudotyped viruses bearing either GPCL84N or GPCK88E decreased sharply in multiple cell types,while L107F and H170S had only mild effects on infectivity.Using biolayer light interferometry assay,we found that all four mutants had decreased binding affinity to LAMP1,in the order of binding affinity being L84 N>L107F>K88E>H170S.The four amino acid loci identified for the first time in this study have important reference significance for the in-depth investigation of the mechanism of receptor switching and immune escape of LASV occurrence and the development of reserve anti-LASV infection drugs.
文摘Nasopharyngeal carcinoma(NPC)is a malignant tumor arising from the nasopharyngeal epithelium.It consists of undifferentiated squamous cells in the nasopharynx.This type of epithelial cell neoplasm is globally distributed,with the highest prevalence observed in certain regions of the world.It has been known since ancient times.The incidence of NPC is steadily decreasing as data on the molecular factors involved in the pathogenesis of NPC accumulate.Glycoproteins are characterized by polymers of saccharides attached to the amino acid sequences of proteins during the process of glycosylation.They are present in all animal cells and are especially abundant on the surface of tumor cells.Alterations in expression of cellular glycoproteins have recently attracted attention as a key component of neoplastic progression.Tumor-associated glycoproteins may serve as a hallmark of cancer cells and thus represent novel diagnostic and even therapeutic targets.Interest in the role of glycoproteins in cancer in general and specifically in NPC pathology has steadily increased over the past fifty years,reaching over thousands and two hundred publications in the last five years,respectively.Here,data on a specific class of proteins,glycoproteins,involved in tumorigenesis of NPCs are summarized,with a focus on a few of the best-studied ones.Relevant studies performed mainly in the last five years were retrieved and collected through the PubMed system.
文摘介绍了一个新的基于优化推导出的核偏最小二乘(kernel partial least squares,K-PLS)的算法原理和实现步骤,并且给出了利用K-PLS法构建P-糖蛋白(P-glycoprotein,P-gp)黄酮类抑制剂的定量构效关系(QSAR)模型.利用该方法结合几个简单的分子拓扑参数,构建了具有高准确率的预测模型.该模型将有助于P-gp黄酮类抑制剂的虚拟筛选和理性设计.结果证明K-PLS是一个十分稳定可靠的方法,将会在化学计量学领域得到较好的应用和推广.
文摘肿瘤多药耐药性(multiple drug resistance,MDR)的发生往往伴随着多药耐药基因如MDR1、MRP1和BCRP等高表达,其中MDR1基因编码的P-糖蛋白(P-glycoprotein,P-gp)是目前公认可以诱发癌细胞发生MDR的重要分子。传统研究认为P-gp主要是作为一个药物泵将化疗药物从细胞内排出从而导致MDR。然而系列研究发现,除了介导MDR以外,P-gp还能够调节癌细胞的生长、增殖、凋亡、迁移和侵袭等其他生物学行为;而且研究表明P-gp的这些作用可以依赖,也可以不依赖于其药物泵的功能。这些结果表明P-gp能够通过一些新的机制促进肿瘤的进展。本文主要针对P-gp在促进肿瘤进展中的作用进行综述。
基金supported by the National Natural Science Foundation of China,No.81171178
文摘Myelin-associated glycoprotein（MAG） inhibits the growth of neurites from nerve cells. Extraction and purification of MAG require complex operations; therefore, we attempted to determine whether commercially available MAG-Fc can replace endogenous MAG for research purposes. Immunofluorescence using specific antibodies against MAG, Nogo receptor（NgR） and paired immunoglobulin-like receptor B（PirB） was used to determine whether MAG-Fc can be endocytosed by neuro-2a cells. In addition, neurite outgrowth of neuro-2a cells treated with different doses of MAG-Fc was evaluated. Enzyme linked immunosorbent assays were used to measure RhoA activity. Western blot assays were conducted to assess Rho-associated protein kinase（ROCK） phosphorylation. Neuro-2a cells expressed NgR and PirB, and MAG-Fc could be endocytosed by binding to NgR and PirB. This activated intracellular signaling pathways to increase RhoA activity and ROCK phosphorylation, ultimately inhibiting neurite outgrowth. These findings not only verify that MAG-Fc can inhibit the growth of neural neurites by activating RhoA signaling pathways, similarly to endogenous MAG, but also clearly demonstrate that commercial MAG-Fc is suitable for experimental studies of neurite outgrowth.
文摘Estrus-associated glycoprotein (EGP) is a special protein in oviductal fluid which appears before ovulation and fertilization and disappears after the embryo passes into the uterus. One-and two dimensional SDS-PAGE and Western blotting with monoclonal antibody or peanut agglutinin were used to characterize the glycoprotein,The specificity of the marking agents enabled the study to proceed without purification. EGP was found to include two proteins: one is acidic with a pH of 4.5 while the other is basic with a pH of 8.0 The molecular weights of their subunits are the same, that is 110 kD. This study may shed light on the mechanism of reproductive Process and be helpful to the development of a more cffective culture medium for in vitro culture of early embryo.
基金supported by grants from the National Natural Science Foundation of China (81471218 and 81771300)the Natural Science Foundation of Guangdong Province, China (2017A030313853)
文摘Immunoglobulin G against myelin oligodendrocyte glycoprotein(MOG-Ig G) is detectable in neuromyelitis optica spectrum disorder(NMOSD) without aquaporin-4 Ig G(AQP4-Ig G), but its pathogenicity remains unclear.In this study, we explored the pathogenic mechanisms of MOG-Ig G in vitro and in vivo and compared them with those of AQP4-Ig G. MOG-Ig G-positive serum induced complement activation and cell death in human embryonic kidney(HEK)-293 T cells transfected with human MOG. In C57 BL/6 mice and Sprague-Dawley rats, MOG-Ig G only caused lesions in the presence of complement. Interestingly, AQP4-Ig G induced astroglial damage, while MOGIg G mainly caused myelin loss. MOG-Ig G also induced astrocyte damage in mouse brains in the presence ofcomplement. Importantly, we also observed ultrastructural changes induced by MOG-Ig G and AQP4-Ig G. These findings suggest that MOG-Ig G directly mediates cell death by activating complement in vitro and producing NMOSDlike lesions in vivo. AQP4-Ig G directly targets astrocytes,while MOG-Ig G mainly damages oligodendrocytes.
文摘During mammalian fertilisation, the zona pellucida （ZP） matrix surrounding the oocyte is responsible for the binding of the spermatozoa to the oocyte and induction of the acrosome reaction （AR） in the ZP-bound spermatozoon. The AR is crucial for the penetration of the ZP matrix by spermatozoa. The ZP matrix in mice is composed of three glycoproteins designated ZP1, ZP2 and ZP3, whereas in humans, it is composed of four （ZP1, ZP2, ZP3 and ZP4）. ZP3 acts as the putative primary sperm receptor and is responsible for AR induction in mice, whereas in humans （in addition to ZP3）, ZP1 and ZP4 also induce the AR. The ability of ZP3 to induce the AR resides in its C-terminal fragment. O-linked glycans are critical for the murine ZP3-mediated AR. However, N-linked glycans of human ZP1, ZP3 and ZP4 have important roles in the induction of the AR. Studies with pharmacological inhibitors showed that the ZP3-induced AR involves the activation of the Gi-coupled receptor pathway, whereas ZP1- and ZP4-mediated ARs are independent of this pathway. The ZP3-induced AR involves the activation of T-type voltage-operated calcium channels （VOCCs）, whereas ZP1- and ZP4-induced ARs involve both T- and L-type VOCCs. To conclude, in mice, ZP3 is primarily responsible for the binding of capacitated spermatozoa to the ZP matrix and induction of the AR, whereas in humans （in addition to ZP3）, ZP1 and ZP4 also participate in these stages of fertilisation.
文摘Gynogenetic silver crucian carp, Carassius auratus gibelio, is an intriguing model system. In the present work, a systemic study has been initiated by introducing suppression subtractive hybridization technique into this model system to identify the differentially expressed genes in oocytes between gynogenetic silver crucian carp and its closely related gonochoristic color crucian carp. Five differential cDNA fragments were identified from the preliminary screening, and two of them are ZP3 homologues. Moreover, the full length ZP3 cDNAs were cloned from their oocyte cDNA libraries. The length of ZP3 cDNAs were 1378 bp for gyno-carp and 1367 bp for gono-carp, and they can be translated into proteins with 435 amino acids. Obvious differences are not only in the composition of amino acids, but also in the number of potential O-linked oligosaccharide sites. In addition, gyno-carp ZP3 amino acid sequence has an unexpected higher identity value with common carp (83.5%) than that with the closely related gono-carp (74.7%). The unique homology may be originated from the ancient hybridization. Northern blot analysis confirmed that expression of the ZP3 gene occurred exclusively in the oocytes. Because O-linked oligosaccharides on ZP3 have been demonstrated to play very important roles in fertilization, it is suggested that the extra O-linked glycosylation sites may be related to the unique sperm-egg recognition mechanism in gynogenesis.
